(1) Field of the Invention
The present invention relates to a method for testing for the presence of metastatic human tumor cells by determining the level of Human Leukocyte Antigen (HLA) in the tumor cells. In particular the present invention relates to a method which uses a bacterial toxin or subunit thereof which selectively binds the HLA to provide a basis For the detection and level of activity.
(2) Prior Art
In 1865, Trousseau observed a high incidence of venous thrombosis in patients with gastric carcinoma and described the syndrome which bears his name (Trousseau, A., In Clinique Medicale de l'Hotel-Dieu de Paris; Paris, Balliere, 3:654 (1865)). A considerable body of evidence supports an association between cancer and thromboembolic disorders (Rickles, F. R., et al., Blood 62:14-31 (1983)) and elements of the hemostatic system (i.e. platelets, thrombin and fibrin) are proposed as causal for tumor cell metastasis (Weiss, L., et al., Clin. Expl. Metas. 7:127-167 (1989)). Activated platelets may enhance tumor cell adhesion to the vessel wall (Honn, K. V., et al., Biochem. Pharm. 34:235-241 (1985)) and induce endothelial cell retraction (Honn, K. V., et al., FASEB. J. 3:2285-2293 (1989)) while fibrin may aid tumor cells to escape the cellular immune system (Gorelik, E., Cancer Res. 47:809-815 (1987)). Tumor cell activation of platelets and generation of fibrin may require thrombin. Therefore, the identification and isolation of the tumor cell prothrombogenic protein(s) responsible for thrombin generation are of considerable interest.
At least four separate factors are thought to mediate tumor cell induced thrombin generation. The first is tissue factor, a transmembrane glycoprotein and receptor, also associated with normal tissue (Broze, G. J., et al., J. Biol. Chem. 260:10917-10920 (1985); and Buha, A., et al., Proc. Natl. Acad. Sci. USA 83:299-302 (1986)). The second, cancer procoagulant, is a cysteine proteinase that directly activates factor X (Gordon, S. G., et al., J. Clin. Invest. 67:1665-1671 (1981)). The third is a protein termed platelet aggregating activity/procoagulant activity (PAA/PCA) isolated from solid tumors or from tumor cells grown in culture which lacks proteolytic activity and is dependent upon factor X for activity (Cavanaugh, P. G., et al., Thromb. Res. 37:309-326 (1985)). More recently, a factor Xa receptor has been identified on some tumor cells (Sakai, T., et al., J. Biol. Chem. 265:9105-9113 (1990)) .
It is important to know if solid tumors are metastatic. If the tumor is not metastatic then the tumor can be removed. If the tumor cell is metastatic then various forms of radical surgery, chemotherapy and radiation may be indicated. It is important that there be a reliable test for metastatic tumor cells.